Minocycline compounds and methods of use thereof

ABSTRACT

Methods and compositions for using a tetracycline compound to treat bacterial infections are described. In one embodiment, for example, the invention provides a method of treating a subject for an infection, comprising administering to said subject an effective amount of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, such that said subject is treated, wherein said infection is selected from the group consisting of MSSA, MRSA, B-streptococci, Viridans Streptococci, Enterococcus, or combinations thereof.

RELATED APPLICATIONS

This application is a continuation application of U.S. Ser. No.14/995,896, filed on Feb. 2, 2016, which is a continuation of U.S.patent application Ser. No. 14/258,847, filed on Apr. 22, 2014, nowissued as U.S. Pat. No. 9,265,740 on Feb. 23, 2016; which is acontinuation of U.S. patent application Ser. No. 12/398,980, filed onMar. 5, 2009, now abandoned; which claims the benefit of the filing dateunder 35 U.S.C. 119(e) to U.S. Provisional Application No. 61/068,180,filed on Mar. 5, 2008, entitled “Methods of Treating Infectious UsingTetracycline Compounds.” The entire contents of each of the foregoingapplications are incorporated herein by reference.

BACKGROUND

The development of the tetracycline antibiotics was the direct result ofa systematic screening of soil specimens collected from many parts ofthe world for evidence of microorganisms capable of producingbacteriocidal and/or bacteriostatic compositions. The first of thesenovel compounds was introduced in 1948 under the name chlortetracycline.Two years later, oxytetracycline became available. The elucidation ofthe chemical structure of these compounds confirmed their similarity andfurnished the analytical basis for the production of a third member ofthis group in 1952, tetracycline. A new family of minocycline compounds,without the ring-attached methyl group present in earlier tetracyclines,was prepared in 1957 and became publicly available in 1967; andminocycline was in use by 1972.

Recently, research efforts have focused on developing new tetracyclineantibiotic compositions effective under varying therapeutic conditionsand routes of administration. New tetracycline analogues have also beeninvestigated which may prove to be equal to or more effective than theoriginally introduced minocycline compounds. Examples include U.S. Pat.Nos. 2,980,584; 2,990,331; 3,062,717; 3,165,531; 3,454,697; 3,557,280;3,674,859; 3,957,980; 4,018,889; 4,024,272; and 4,126,680. These patentsare representative of the range of pharmaceutically active tetracyclineand tetracycline analogue compositions.

Historically, soon after their initial development and introduction, thetetracyclines were found to be highly effective pharmacologicallyagainst rickettsiae; a number of grain-positive and gram-negativebacteria; and the agents responsible for lymphogranuloma venereum,inclusion conjunctivitis, and psittacosis. Hence, tetracyclines becameknown as “broad spectrum” antibiotics. With the subsequent establishmentof their in vitro antimicrobial activity, effectiveness in experimentalinfections, and pharmacological properties, the tetracyclines as a classrapidly became widely used for therapeutic purposes. However, thiswidespread use of tetracyclines for both major and minor illnesses anddiseases led directly to the emergence of resistance to theseantibiotics even among highly susceptible bacterial species bothcommensal and pathogenic (e.g., pneumococci and Salmonella). The rise oftetracycline-resistant organisms has resulted in a general decline inuse of tetracyclines and tetracycline analogue compositions asantibiotics of choice. In addition, other antibacterial agents have alsobeen over used creating strains of multiple drug resistant bacteria.Therefore, there is a need for effective antibacterial agents for thetreatment of bacterial infections.

SUMMARY OF THE INVENTION

In one embodiment, the invention pertains, at least in part, to a methodof treating a subject, comprising administering to the subject aneffective amount of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocyclineor a salt thereof, wherein said tetracycline compound has an efficacy,greater than linezolid for the treatment of bacterial infections.

In another embodiment, the invention also pertains, at least in part, toa method of treating a subject for an infection, by administering to thesubject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof; wherein the tetracyclinecompound has a clinical success rate of about 93.7% or greater fortreating infections of methicillin-susceptible Staphylococcus aureus(MSSA), methicillin-resistant Staphylococcus aureus (MRSA),B-streptococci, gram-negative bacteria (e.g., gram-negative rods (GNR)),Viridans Streptococci, Enterococcus, gram-positive bacteria (e.g.,gram-positive anaerobes), or combinations thereof.

In another embodiment, the invention also pertains to a method oftreating a subject for an infection, comprising administering to saidsubject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof, such that said subject istreated, wherein said infection is selected from the group consisting ofMSSA, MRSA, B-streptococci, Viridans Streptococci, Enterococcus, andcombinations thereof.

In another embodiment, said salt is a hydrochloride salt. In anotherembodiment, said salt is a tosylate salt.

In another embodiment, said subject is a human. In another embodiment,said subject is suffering from injury, abscess, ulcer, or cellulitis. Inanother embodiment, said injury is a trauma, surgery, bite, or burn.

In another embodiment, said 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered orally. In anotherembodiment, said 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline isadministered intravenously.

In another embodiment, said 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered orally at dose of about 100mg to about 300 mg per day. In another embodiment, said9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is administeredorally at a dose of about 200 mg per day. In another embodiment, said9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is administeredintravenously at a dose of about 50 mg to about 150 mg per day. Inanother embodiment, said 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered intravenously at a dose ofabout 100 mg per day.

In another embodiment, said 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline has a clinical success rate of treating aninfection of greater than about 93.2%. In another embodiment, said9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline has amicrobiologically evaluable clinical success rate of treating aninfection of greater than about 93.7%.

In another embodiment, the present invention provides a method oftreating a subject for an infection, comprising administering to saidsubject an oral dose of about 100 mg to about 300 mg per day of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof,such that said subject is treated, wherein said infection is selectedfrom the group consisting of MSSA, MRSA, B-streptococci, ViridansStreptococci, Enterococcus, and combinations thereof, and furtherwherein said subject is in need of treatment thereof.

In another embodiment, the present invention provides a method oftreating a subject for an infection, comprising administering to saidsubject an intravenous dose of about 50 mg to about 150 mg per day of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof,such that said subject is treated, wherein said infection is selectedfrom the group consisting of MSSA, MRSA, B-streptococci, ViridansStreptococci, Enterococcus, and combinations thereof, and furtherwherein said subject is in need of treatment thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising from about 100 to about 300 mg of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof anda pharmaceutically acceptable carrier for oral administration. Inanother embodiment, said composition comprises about 200 mg of said9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising from about 50 to about 150 mg of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof anda pharmaceutically acceptable carrier for intravenous administration. Inanother embodiment, said composition comprises about 100 mg of said9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline.

DETAILED DESCRIPTION OF THE INVENTION

The invention pertains, at least in part, to the discovery that9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is effective to treatbacterial infections, including methicillin-susceptible Staphylococcusaureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA),B-streptococci, gram-negative bacteria (e.g., gram-negative rods (GNR)),Viridans Streptococci, Enterococcus, gram-positive bacteria (e.g.,gram-positive anaerobes), or combinations thereof.9-[2,2-dimethyl-propyl amino)-methyl]-minocycline (compound 1) is apotent antibiotic with a greater clinical success rate than linezolid(e.g.,N-[[3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl]methyl]acetamide,Zyvox™). The structure of linezolid is:

The invention pertains, at least in part, to a method of treating asubject, comprising administering to said subject an effective amount ofcompound 1 or a salt thereof, such that said subject is treated, whereinthe tetracycline compound has an efficacy greater than linezolid.

The term “tetracycline compound” includes compounds with a four-ringcore structure similar to that of tetracycline and its analogs (e.g.,minocycline, sancycline, doxycycline, methacycline, etc.). Thetetracycline compound of the invention is a 9-aminomethyl tetracyclinecompound, e.g., a compound substituted at the 9-position with anaminomethyl moiety (e.g., —CH₂—NR′R″, wherein R′ and R″ can each behydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl alkyl, etc.). Thetetracycline compound is 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline (compound 1), or a salt thereof. Thestructure of compound 1 is:

In a further embodiment, 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered orally as the free base or asthe tosylate salt. In another embodiment, 9[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered intravenously as thehydrochloride salt.

The term “treating” or “treatment” refers to the amelioration,eradication, or diminishment of one or more symptoms of the disorder,e.g., a bacterial infection, to be treated. In certain embodiments, thedisorder term includes the eradication of bacteria associated with theinfection to be treated.

The term “prophylaxis” means to prevent or reduce the risk of bacterialinfection.

The term “resistance” or “resistant” refers to the antibiotic/organismstandards as defined by the Clinical and Laboratories StandardsInstitute (CLSI) and/or the Food and Drug Administration (FDA).

In a further embodiment, the infection may be an infection caused bygram-positive pathogens (e.g., methicillin-susceptible Staphylococcusaureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA),Enterococcus faecalis, Enterococcus faecium, vancomycin-resistantEnterococcus faecium (VRE), Streptococcus pneumoniae,penicillin-resistant Streptococcus pneumoniae (PRSP), Streptococcuspyogenes, Streptococcus agalactiae, etc.), gram-negative pathogens(e.g., Haemophilus influenzae, Moraxella catarrhalis, Neisseriagonorrhoeae, Escherichia coli, Shigella spp., Salmonella spp.,Klebsiella pneumoniae, Enterobacter aerogenes, Enterobacter cloacae,Serratia marcescens, Acinetobacter baumannii, Stenotrophomonasmaltophilia, etc.), anaerobic pathogens (e.g., Bacteroides fragilis,Clostridium perfringens, etc.) and/or atypical pathogens (e.g.,Chlamydia pneumoniae, Legionella pneumophila, etc.).

The infection may be resistant to other antibiotics, such as penicillinor tetracycline. Examples of bacterial infections which can be treatedwith the compounds of the invention include infections of MSSA,methicillin-resistant Staphylococcus aureus (MRSA) including bothhospital-associated and community-associated MRSA, streptococci (e.g.,Streptococcus pneumoniae, Streptococcus pneumoniae (PRSP), Streptococcuspyogenes, and Streptococcus agalactiae), gram-negative bacteria (e.g.,gram-negative rods (GNR)), Viridans Streptococci, Enterococcus,gram-positive bacteria (e.g., grain-positive anaerobes), or combinationsthereof.

In another embodiment, the infection is a hospital-associated MRSAinfection. In another embodiment, the infection is acommunity-associated MRSA infection.

In another embodiment, the infection is an acute bacterial infectionprompting or occurring during hospitalization.

In another embodiment, the present invention provides a method oftreating a subject for an infection, comprising administering to saidsubject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof, such that said subject istreated, wherein said infection is selected from the group consisting ofMSSA, MRSA, B-streptococci, Viridans Streptococci, Enterococcus, mixedgram-positve cocci, mixed gram-positive cocci/gram-negative rods orcombinations thereof.

In another embodiment, the present invention provides a method oftreating a subject for an infection, comprising administering to saidsubject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof, such that said subject istreated, wherein said infection is selected from the group consisting ofMSSA, MRSA, B-streptococci, mixed gram-positive cocci, mixedgram-positive cocci/gram-negative rods, or combinations thereof.

In another embodiment, the present invention provides a method oftreating a subject for an infection, comprising administering to saidsubject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof, such that said subject istreated, wherein said infection is selected from the group consisting ofMSSA, MRSA, B-streptococci, or combinations thereof.

In another embodiment, the present invention provides a method oftreating a subject for an infection, comprising administering to saidsubject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof, such that said subject istreated, wherein said infection is selected from the group consisting ofhospital-associated MRSA and community-associated MRSA.

In another further embodiment, the subject may be suffering fromcomplicated skin and skin structure infections (CSSSI). Such CSSSIinfections may result in hospitalization or occur duringhospitalization.

In another further embodiment, the subject may be suffering fromdiabetic foot infections. Such diabetic foot infections may result inhospitalization or occur during hospitalization.

In another further embodiment, the subject may be suffering fromcommunity- or hospital-acquired pneumonia. Such community- orhospital-acquired pneumonia may result in hospitalization or occurduring hospitalization.

In another further embodiment, the subject may be suffering fromintra-abdominal infection. Such an intra-abdominal infection may resultin hospitalization or occur during hospitalization.

In another further embodiment, the subject may be suffering from aninjury (e.g., trauma, surgery, bite, removal of foreign body or burn),abscess (e.g., major or minor abscess), ulcer (e.g., lower or upperextremity ulcer), or cellulitis (which may be accompanied by acomorbidity, such as diabetes mellitus, hepatitis C, substance abuse,cardiovascular disease (including coronary artery disease or peripheralvascular disease), vascular insufficiency, or immunosupressive therapy).Examples of major abscesses includes those which require drainage orinvolve subcutaneous or deeper tissues. An example of a burn includes aburn over less than 5% of the subject's body.

The term “subject” includes animals capable of suffering from abacterial infection. Examples of subjects include animals such as farmanimals (e.g., cows, pigs, horses, goats, rabbits, sheep, etc.), labanimals (mice, rats, etc.), pets (e.g., dogs, cats, ferrets, etc.), andprimates (e.g., monkeys, gorillas, chimpanzees, and humans).

The tetracycline compound may be administered by any route which allowsthe compound to perform its intended function, e.g., treat a bacterialinfection. Examples of routes include orally, intravenously, andtopically. Preferably, the compound is administered orally orintravenously.

The term “effective amount” includes the amount of the tetracyclinecompound needed to treat a bacterial infection. For example, aneffective amount describes an efficacious level sufficient to achievethe desired therapeutic effect through the killing of bacteria and/orinhibition of bacterial growth. Preferably, the bacterial infection istreated when the pathogen (e.g., bacteria) is eradicated.

The term “evaluable clinical success” refers to a clinical trialparticipant who:

(1) did not meet any criteria for evaluable clinical failure;

(2) did not receive potentially effective non-study antibiotics for anyother reason; and

(3) the blinded evaluator indicated at the test of cure evaluation thatthe infection had sufficiently resolved such that antibiotics were notneeded.

The term “evaluable clinical failure” refers to a clinical trialparticipant who met any one of the following criteria: the blindedevaluator discontinued study drug and indicated that the infection hadresponded inadequately such that alternative antibiotic(s) were needed;the blinded evaluator discontinued study drug because of an adverseevent that was assessed as probably or possibly drug-related; theprimary site of infection was surgically removed; or the subject had noevaluation after the end of intravenous treatment.

The term “clinical success rate” refers to the number of evaluableclinical successes divided by the total number of population in thetrial.

The term “microbiologically evaluable clinical success rate” refers tothose who met the definition of evaluable clinical success and had aninfecting pathogen at baseline.

In one embodiment, the effective amount of the tetracycline compound,e.g. 9[(2,2-dimethyl-propyl amino)-methyl]-minocycline, whenadministered orally is from about 100 to about 300 mg, about 110 toabout 290 mg, from about 120 to about 280 mg, from about 130 to about270 mg, from about 140 to about 260 mg, from about 150 to about 250 mg,from about 160 to about 240 mg, from about 170 mg to about 230 mg, fromabout 180 mg to about 220 mg, from about 190 mg to about 210 mg, orabout 200 mg. The compound may be administered as a salt (e.g., tosylatesalt) or as a free base.

In another embodiment, the effective amount of the tetracyclinecompound, e.g., 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline, whenadministered intravenously is from about 50 to about 200 mg, from about50 to about 150 mg, from about 60 to about 140 mg, from about 70 mg toabout 130 mg, from about 80 mg to about 120 mg, from about 90 mg toabout 110 mg, or about 100 mg.

It is to be understood that wherever values and ranges are providedherein, e.g., in ages of subject populations, dosages, and blood levels,all values and ranges encompassed by these values and ranges, are meantto be encompassed within the scope of the present invention. Moreover,all values in these values and ranges may also be the upper or lowerlimits of a range.

In another embodiment, the tetracycline compound may be administeredonce per day, either intravenously or orally.

In a further embodiment, the tetracycline compound has a greaterclinical success rate than linezolid (e.g.,N-[[3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl]methyl]acetamide),when the linezolid is administered at 600 mg orally or 600 mgintravenously every 12 hours.

In a further embodiment, the compound of the invention has a clinicalsuccess rate of greater than about 93.2%, greater than about 95%,greater than about 96%, greater than about 97%, or greater than about98% when treating a bacterial infection. For example, a clinical successrate of about 93.7% or greater. Such bacterial infections include, e.g.,MSSA, methicillin-resistant Staphylococcus aureus (MRSA),B-streptococci, GNR, Viridans Streptococci, Enterococcus, gram-positiveanaerobes, or combinations thereof. In contrast, linezolid was found tohave a clinical success rate of 93.7% when treating infections of thesebacteria.

In another further embodiment, the compound of the invention has amicrobiologically evaluable clinical success rate of greater than about93.7%, greater than about 95%, greater than about 96%, greater thanabout 97%, or about 97.4% or greater, when treating a bacterialinfection. Such bacterial infections include, e.g., MSSA,methicillin-resistant Staphylococcus aureus (MRSA), B. streptococci,GNR, Viridans Streptococci, Enterococeus, gram-positive anaerobes, orcombinations thereof.

In a further embodiment, the invention pertains to a method for treatinga MSSA infection comprising administering an effective amount of anantibiotic compound, wherein said compound has a clinical success rateof greater than 91%. In a further embodiment, the antibiotic compound isa tetracycline compound, e.g., 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline. In contrast to linezolid which has aclinical success rate of 91% against. MSSA (as determined in the trialsdescribed in the Exemplification of the Invention),9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline has a clinicalsuccess rate of 93% against MSSA.

In another further embodiment, the invention pertains to a method fortreating MRSA infection comprising administering an effective amount ofan antibiotic compound, wherein said compound has a clinical successrate of greater than 93%. In a further embodiment, the antibioticcompound is a tetracycline compound, e.g., 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline. In contrast to linezolid which has aclinical success rate of 93% against MRSA (as determined in the trialsdescribed in the Exemplification of the Invention),9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline has a clinicalsuccess rate of 100% against MRSA.

In another further embodiment, the invention pertains to a method fortreating a B. streptococci infection comprising administering aneffective amount of an antibiotic compound, wherein said compound has aclinical success rate of greater than 0%, greater than 10%, greater than20%, greater than 30%, greater than 50%, greater than 70%, greater than80%, greater than 90%, greater than 91%, greater than 92%, greater thanabout 93%, greater than about 94%, greater than about 95%, greater thanabout 96%, greater than about 97%, greater than about 98%, greater thanabout 99%, or about 100%. In a further embodiment, the antibioticcompound is a tetracycline compound, e.g., 9[(2,2-dimethyl-propylamino)-methyl]-minocycline. In contrast to linezolid which has aclinical success rate of 0% against B. streptococci (as determined inthe trials described in the Exemplification of the Invention),9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline has a clinicalsuccess rate of 100% against B. streptococci.

In yet another further embodiment, the invention also pertains to amethod of treating a subject for an infection. The method includesadministering to the subject an effective amount of9-[(2,2-dimethyl-propyl amino)-methyl]minocycline or salt thereof.Advantageously, the 9-[(2,2-dimethyl-propyl amino)-methyl]-minocyclinehas clinical success rate of about 93.7% or greater for treatinginfections. Examples of infections which can be treated using themethods of the invention include, but are not limited to, MSSA, MRSA,B-streptococci, GNR, Viridans Streptococci, Enterococcus, gram-positiveanaerobes, or combinations thereof.

In a further embodiment, the salt is a tosylate salt or a free base whenadministered orally, or a hydrochloride salt when administeredintravenously.

The invention also pertains, at least in part, to a method of treating asubject for an infection (e.g., a bacterial infection), by orallyadministering to said subject about 200 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt, such that the subject istreated for the infection.

The invention also pertains, at least in part, to a method of treating asubject for an infection (e.g., a bacterial infection), by intravenouslyadministering to the subject about 100 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, hydrochloride salt, such that the subject istreated for the infection.

In another embodiment, the invention also pertains to a method oftreating a subject for an infection (e.g., a bacterial infection), byorally administering to the subject about 200 mg of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline, free base, such thatthe subject is treated for the infection.

In one example, a subject is treated intravenously followed by an oralstep down. In another embodiment, the present invention provides amethod of treating a subject for an infection, comprising administeringto said subject an effective amount of compound 1 or a salt thereofwherein said subject is initially treated about 1 week or about 2 weeksor about 3 weeks intravenously followed by about 1 week or about 2 weeksor about 3 weeks of oral treatment, such that said subject is treated.

In another embodiment, the present invention provides a method oftreating a subject for an infection, comprising administering to saidsubject an effective amount of compound 1 or a salt thereof wherein saidsubject initially treated intravenously has elevated compound 1 bloodlevels followed by reduced compound 1 blood levels with oral treatment,such that said subject is treated.

In another embodiment, the present invention provides a method oftreating a subject for an infection, comprising administering to saidsubject an effective amount of compound 1 or a salt thereof for morethan 28 days, up to and including about 28 days, up to and includingabout 21 days, up to and including about 14 days, up to and includingabout 10 days, up to and including about 9 days, up to and includingabout 8 days, or up to and including about 7 days, such that saidsubject is treated.

Pharmaceutical Compositions of the Invention

The invention also pertains to pharmaceutical compositions comprising atherapeutically effective amount of a tetracycline compound (e.g., a9-aminomethyl tetracycline compound, e.g., 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline) or a salt thereof and, optionally, apharmaceutically acceptable carrier.

In a further embodiment, the invention pertains to a pharmaceuticalcomposition comprising from about 100 to about 300 mg of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt there ofand a pharmaceutically acceptable carrier. In a further embodiment, thepharmaceutically acceptable carrier is acceptable for oraladministration. In another further embodiment, the tetracycline compoundis a free base or a tosylate salt.

In yet another further embodiment, the composition comprises from about110 to about 290 mg, from about 120 to about 280 mg, from about 130 toabout 270 mg, from about 140 to about 260 mg, from about 150 to about250 mg, from about 160 to about 240 mg, from about 170 mg to about 230mg, from about 180 mg to about 220 mg, from about 190 mg to about 210mg, or about 200 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline.

In another embodiment, the invention also pertains to a pharmaceuticalcomposition comprising from about 50 to about 150 mg of9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof(e.g., a hydrochloride salt) and a pharmaceutically acceptable carriersuitable for intravenous administration.

In yet another further embodiment, the composition comprises from about50 to about 150 mg, from about 60 to about 140 mg, from about 70 mg toabout 130 mg, from about 80 mg to about 120 mg, from about 90 mg toabout 110 mg, or about 100 mg of 9[(2,2-dimethyl-propylamino)-methyl]-minocycline.

The language “pharmaceutically acceptable carrier” includes substancescapable of being coadministered with the tetracycline compound of theinvention, e.g., 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline, andwhich allow the tetracycline compound to perform its intended function,e.g., treat or prevent a bacterial infection. Suitable pharmaceuticallyacceptable carriers include but are not limited to water, saltsolutions, alcohol, vegetable oils, polyethylene glycols, gelatin,lactose, amylose, magnesium stearate, talc, silicic acid, viscousparaffin, perfume oil, fatty acid monoglycerides and diglycerides,petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, colorings, flavorings and/oraromatic substances and the like which do not deleteriously react withthe active compounds of the invention.

The tetracycline compounds of the invention that are basic in nature arecapable of forming a wide variety of salts with various inorganic andorganic acids. The acids that may be used to prepare pharmaceuticallyacceptable acid addition salts of the minocycline compounds of theinvention that are basic in nature are those that form nontoxic acidaddition salts, i.e., salts containing pharmaceutically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand palmoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.Although such salts must be pharmaceutically acceptable foradministration to a subject, e.g., a mammal, it is often desirable inpractice to initially isolate a minocycline compound of the inventionfrom the reaction mixture as a pharmaceutically unacceptable salt andthen simply convert the latter back to the free base compound bytreatment with an alkaline reagent and subsequently convert the latterflee base to a pharmaceutically acceptable acid addition salt. The acidaddition salts of the base compounds of this invention are readilyprepared by treating the base compound with a substantially equivalentamount of the chosen mineral or organic acid in an aqueous solventmedium or in a suitable organic solvent, such as methanol or ethanol,Upon careful evaporation of the solvent, the desired solid salt isreadily obtained. Preferably, the tetracycline compound of the inventionis administered as a tosylate (e.g., p-toluenesulfonate) salt or as afreebase orally or as a hydrochloride salt intravenously.

The tetracycline compounds of the invention and pharmaceuticallyacceptable salts thereof can be administered via either the oral,parenteral or topical routes. In general, these compounds are mostdesirably administered in effective dosages, depending upon the weightand condition of the subject being treated and the particular route ofadministration chosen. Variations may occur depending upon the speciesof the subject being treated and its individual response to saidmedicament, as well as on the type of pharmaceutical formulation chosenand the time period and interval at which such administration is carriedout.

The pharmaceutical compositions of the invention may be administeredalone or in combination with other known compositions for treatingtetracycline responsive states in a subject, e.g., a mammal. Mammalsinclude pets (e.g., cats, dogs, ferrets, etc.), farm animals (cows,sheep, pigs, horses, goats, etc.), lab animals (rats, mice, monkeys,etc.), and primates (chimpanzees, humans, gorillas). The language “incombination with” a known composition is intended to includesimultaneous administration of the composition of the invention and theknown composition, administration of the composition of the inventionfirst, followed by the known composition and administration of the knowncomposition first, followed by the composition of the invention. Any ofthe therapeutically composition known in the art for treatingtetracycline responsive states can be used in the methods of theinvention.

The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers or diluents by anyof the routes previously mentioned, and the administration may becarried out in single or multiple doses. For example, the noveltherapeutic agents of this invention can be administered advantageouslyin a wide variety of different dosage forms, i.e., they may be combinedwith various pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, troches, hard candies, powders, sprays,creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various non-toxic organic solvents, etc. Moreover,oral pharmaceutical compositions can be suitably sweetened and/orflavored. In general, the therapeutically-effective tetracyclinecompounds of this invention are present in such dosage forms atconcentration levels ranging from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (and preferably corn, potato or tapioca starch), alginicacid and certain complex silicates, together with granulation binderslike polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in gelatin capsules;preferred materials in this connection also include lactose or milksugar as well as high molecular weight polyethylene glycols.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient may be combined with varioussweetening or flavoring agents, coloring matter or dyes, and, if sodesired, emulsifying and/or suspending agents as well, together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouslike combinations thereof.

For parenteral administration (including intraperitoneal, subcutaneous,intravenous, intradermal or intramuscular infection), solutions of atherapeutic compound of the present invention in either sesame or peanutoil or in aqueous propylene glycol may be employed. The aqueoussolutions should be suitably buffered (preferably pH greater than 8) ifnecessary and the liquid diluent first rendered isotonic.

These aqueous solutions are suitable for intravenous injection purposes.The oily solutions are suitable for intraarticular, intramuscular andsubcutaneous injection purposes. The preparation of all these solutionsunder sterile conditions is readily accomplished by standardpharmaceutical techniques well known to those skilled in the art. Forparenteral application, examples of suitable preparations includesolutions, preferably oily or aqueous solutions as well as suspensions,emulsions, or implants, including suppositories. Therapeutic compoundsmay be formulated in sterile form in multiple or single dose formatssuch as being dispersed in a fluid carrier such as sterile physiologicalsaline or 5% saline dextrose solutions commonly used with injectables.

For enteral application, particularly suitable are tablets, dragees orcapsules having talc and/or carbohydrate carrier binder or the like, thecarrier preferably being lactose and/or corn starch and/or potatostarch. A syrup, elixir or the like can be used wherein a sweetenedvehicle is employed. Sustained release compositions can be formulatedincluding those wherein the active component is protected withdifferentially degradable coatings, e.g., by microencapsulation,multiple coatings, etc.

In addition to treatment of human subjects, the therapeutic methods ofthe invention also will have significant veterinary applications, e.g.for treatment of livestock such as cattle, sheep, goats, cows, swine andthe like; poultry such as chickens, ducks, geese, turkeys and the like;horses; and pets such as dogs and cats. Also, the compounds of theinvention may be used to treat non-animal subjects, such as plants.

EXEMPLIFICATION OF THE INVENTION Example 1: Use of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline to Treat Infections

A randomized (1:1), controlled, evaluator-blinded Phase 2 studycomparing 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline(compound 1) and linezolid (Zyvox™) for the treatment of complicatedskin and skin structure infections (CSSSI) was conducted. Patients withCSSSI who required initial intravenous (IV) therapy and met inclusionand exclusion criteria were enrolled at 11 centers in the US and wererandomized to receive either compound 1 (100 mg Q24 h IV with 200 mg Q24h oral step-down) or linezolid (600 mg Q12 h IV with 600 mg Q12 h oralstep-down).

Study Evaluations

All subjects had four structured evaluations: at Enrollment (Baseline);at End of IV Treatment; at End of Treatment; and at 10 to 17 days afterlast dose of treatment (test of cure (TOC) evaluation). In addition, theblinded investigator saw each subject daily while they were on IVtherapy and at least every 3 days while receiving oral treatment todetermine whether to continue current treatment, switch from IV to oraltherapy, or discontinue treatment.

At each of the four structured evaluations, the blinded evaluatorassessed the subject, with particular attention to scoring the findingsat the primary site of infection and obtaining cultures. Clinical andmicrobiologic outcomes were determined using these assessments, Primaryevaluation criteria was safety and tolerability compared with linezolid.Secondary evaluation criteria was efficacy of compound 1 compared tolinezolid, as well as pharmacokinetics of compound 1.

Subjects were randomized on a 1:1 basis to receive either compound 1 orlinezolid. Random assignment of subjects avoids bias and helps ensurethat both known and unknown risk factors are distributed evenly betweentreatment groups.

At each scheduled evaluation, the blinded evaluator examined the primarysite of infection; for patients with multiple non-contiguous areas ofinfection, the blinded evaluator identified the most severely affectedportion at Enrollment and designated that as the primary site ofinfection. The following information was recorded for each patient:maximal linear dimension of area of continuous involvement of infection;maximal linear dimension of ulceration, if present; semi-qualitative(scale of 0 to 3; none, mild, marked, severe) description of infectionfor the following features: erythema, edema/induration, fluctuance,necrotic tissue, purulence (including drainage), and tenderness pain. Inaddition, at the Enrollment Evaluation, the following were also recordedthe anatomical location of the primary site of infection; and theclinical diagnosis of the type of the infection.

In addition, the patients in the study were monitored for adverse events(AE). An adverse event is any untoward medical occurrence temporallyassociated with the use of a medical product in a subject, whether ornot the event is considered causally related to the medical product. AnAE can be a new occurrence or an existing process that increasessignificantly in intensity or frequency.

Patient Inclusion/Exclusion Criteria

Patients were between 18 and 80 years of age. Patients were on effectivebirth-control, or had no potential for childbearing, Patients had aqualifying infection (see below). Patients with any of the followingconditions were not allowed in the trial: pregnant or nursing;previously treated under this protocol; non-qualifying skin/skinstructure infection; allergy to study antibiotics; receivedinvestigational drug within one month; history of chronic livercirrhosis; alanine aminotransferase (ALT) exceeding 2× upper limit ofnormal (ULN) during week prior to enrollment; total bilirubin exceedingULN during week prior to enrollment; total body weight <40 kg or >150kg; known to be HIV positive and meets CDC criteria for AIDS; lifeexpectancy of less than 3 months; required hemodialysis or peritonealdialysis; creatine clearance <30 mL/min; absolute neutrophil count<500/microliter; hypotension (supine systolic BP<90 mmHg) or perfusionabnormalities; required pressors to maintain blood pressure and/oradequate tissue perfusion; received potentially effective systemicantibiotic within 48 hrs; had an infecting pathogen know to beintermediate or resistant to study antibiotics; had confirmed orsuspected non-infectious skin disorder that may potentially interferewith evaluations; or any concomitant condition that would interfere withevaluation or completion of the study.

Qualifying Infections

Examples of skin and soft tissue infections which were qualified to havebeen treated in the study were: Infections associated with trauma (e.g.,traumatic injury (e.g., crush, puncture, laceration, gunshot)); surgicalincisions; animal or human bites, providing the bite caused tissuedamage; infections associated with removable foreign body (e.g.,suppurative phlebitis associated with intravenous catheter sites,infected pacemaker pocket, etc.), and burns, second-degree involving <5%body surface), major abscesses (including carbuncles) which involve thesubcutaneous or deeper tissues and require incision and drainage (ordrained spontaneously), infected acute lower extremity ulcers withco-morbidity, wherein the ulcer is acute i.e., has been persistentlypresent for less than three months, and is accompagnied by at least oneor the following diabetes mellitus requiring an oral hypoglycemic agentor insulin, arterial vascular insufficiency, or venous vascularinsufficiency, or cellulitis with co-morbidity such as diabetes mellitusrequiring an oral hypoglycemic agent or insulin, arterial vascularinsufficiency; venous vascular insufficiency, or immunosuppressivetherapy during the past 3 months.

Drug Administration

Both the investigational drug, compound 1, and the comparator drug,Zyvox™ were administered intravenously and orally. Patients randomizedto linezolid may have received aztreonam IV for suspected or documentedgram-negative infection. Subjects were initially treated with study drugIV and then switched to oral therapy. The expected duration of IVtreatment was up to 7 days; the expected total duration of treatment (IVand oral) was up to 14 days.

For IV administration, the HCl salt of compound 1 for injection wasgiven as 100 mg in 100 ml sterile saline infused over 30 minutes q24 h.For oral administration, compound 1 100 mg capsules were taken fastingas 2 capsules with 8 oz. water q24 h. No food was to be taken for 30 to60 minutes after dosing and no dairy products for 4 hours.

Linezolid (Zyvox™) 600 mg tablets and pre-mixed 600 mg IV infusionsolution (300 ml volume) were obtained from commercial sources.Linezolid 600 mg IV was administered as a 30 minute infusion.

Patients randomized to linezolid may have received aztreonam 2 g IV q 12h for suspected or documented gram-negative infection. Aztreonam wasobtained from commercial sources as a premixed infusion solution (2 g in50 ml) and administered over 30 minutes. No other adjunct topical orsystemic antibiotics were permitted.

Efficacy Analysis

Efficacy analyses were performed on several populations of subjects.Subjects were analyzed for efficacy according to randomization,regardless of treatment administered.

The Intent-to-Treat (ITT) population includes all enrolled subjects whoreceived at least one dose of study medication.

The modified intent-to-Treat (mITT) population comprises all subjects inthe ITT population who have an Infecting Pathogen isolated at prior toadministration of the study compound.

The Clinically Evaluable (CE) population comprises all subjects in theITT population who meet specific criteria such that the clinical outcomeof their infection could be inferred to reflect the effect of the studydrug. The criteria include: have a qualifying skin and skin structureinfection; receive the correct study drug (i.e., as randomized) for atleast five calendar days, have the necessary clinical evaluationsperformed, and did not receive potentially confounding non-studyantibiotics.

The Microbiologically Evaluable (ME) population includes all subjects inthe CE population who had an infecting pathogen at baseline.

Subjects were considered to be an evaluable clinical failure if theymeet any one of the following criteria: the blinded evaluatordiscontinued study drug and indicated that the infection had respondedinadequately such that alternative antibiotic(s) were needed; theblinded evaluator discontinued study drug because of an adverse eventthat was assessed as probably or possibly drug-related; the primary siteof infection was surgically removed; or the subject had no evaluationafter the end of IV treatment.

Subjects were considered to be an evaluable clinical success if theymeet all of the following: did not meet any criteria for evaluableclinical failure; did not receive potentially effective non-studyantibiotics for any other reason; and at the test of cure evaluation theblinded evaluator indicates that the infection had sufficiently resolvedsuch that antibiotics were not needed.

Pathogen Classification

An infecting pathogen was defined as an isolate derived from the lastpositive culture taken from the site of infection under study prior toand including day 1.

A persisting pathogen at the site of infection under study was definedas an isolate that was the same genus and species as an infectingpathogen; and was cultured at the Test-of-Cure evaluation from the siteof infection under study.

A superinfecting pathogen at the site of infection under study isdefined as a pathogen meeting all of the following criteria: representeda genus and species not isolated during the Enrollment evaluation, wascultured at any time from the day 3 of treatment to the test of cureevaluation, inclusive; was cultured from a patient who had at least oneinfecting pathogen; and was cultured from a patient who represents a“clinical failure.”

A superinfecting pathogen at a site other than the infection under studyis defined as a pathogen fleeting all of the following criteria:represented a genus and species not isolated during the baselineevaluation; was cultured at any time from day 3 of treatment to the testof cure evaluation, inclusive; and was cultured from a patient who hasan AE of infection at or related to the site from which the organism iscultured.

Microbiological Outcomes

Microbiological response to treatment was determined for each infectingpathogen using the following classification: documented eradication,presumed eradication, documented persistence, presumed persistence, orunknown.

Microbiological response to treatment was determined for each subjectusing the following classification:

Microbiologic Success—all infecting pathogens isolated at baseline wereeradicated or presumed eradicated at the test-of-cure evaluation and nosuperinfecting pathogen was isolated from the site of infection understudy.

Microbiological Failure—persistence or presumed persistence of one ormore infecting pathogens or isolation of a superinfecting pathogen fromthe site of infection under study.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents are considered to be within the scope of this inventionand covered by the claims appended hereto. The contents of allreferences, issued patents, and published patent applications citedthroughout this application are hereby incorporated by reference.

Results

Enrollment: 234 patients over 11 sites. No discontinuations due toelevated liver function tests (LFT)s. No serious adverse events (SAE)s.Interim data and safety monitoring board (DSMB)_review: no safetyissues, blind not broken.

TABLE 1 Subpopulations. Subpopulations Compound 1 Linezolid Allrandomized 118 116 Randomized, treated 111 108 Intent-to-treat 111(100%) 108 (100%)  Modified ITT  82 (73.9%) 78 (72.2%) Clinicallyevaluable  100 (90.1%) 88 (81.5%) Microbiologically Evaluable  75(67.6%) 63 (58.3%) Safety Population 111 (100%) 108 (100%) 

TABLE 2 Demographics. Demographic or Compound 1 Linezolid ParameterMeasure (n = 111) (n = 108) Sex Female 45 (40.5%) 51 (47.2)   Male 66(59.5%) 57 (52.8%) Ethnicity Hispanic 38 (34.2%) 53 (49.1%) Non Hispanic73 (65.8%) 55 (50.9%) Race Caucasian 97 (87.4%) 99 (91.7%) Black 8(7.2%) 6 (5.6%) Asian 4 (3.6%) 1 (0.9%) American Native 0 1 (0.9%) Other2 (1.8%) 1 (0.9%) Age (years) 18-44 51 (45.9%) 50 (46.3%) 45-64 50(45.0%) 48 (44.4%) >64 10 (9.0%)  10 (9.3%)  Age Mean 44.9 45.8 SD 14.0913.32 Min 19 19 Median 46 46 Max 81 76 Weight Mean 84.2 85.0 SD 21.9520.22 Min 45 51 Median 80 80 Max 144 152 BMI (kg/m2) Mean 28.8 29.3 SD6.89 6.80 Min 17 19 Median 28 28 Max 48 52

TABLE 3 Qualifying infections used in the study. Compound 1 LinezolidCategory (n = 111) (n = 108) Injury 21 17 Major Abscess 73 72 Lowerextremity ulcer¹ 9 9 Cellulitis with co-morbidity¹ 8 10 ¹14/18 LE ulcersand 11/18 cellulitis were in diabetics; most of the rest had venousinsufficiency as co-morbidity.

TABLE 4 Maximal dimensions of infections (ITT population). Compound 1Linezolid Type of Infection (n = 111)^(a) (n = 108)^(a) MajorAbscess^(b) 10 (6-16) 7.8 (4.1-13) Infected injury 10.5 (4-31)   7(3-19.5) Cellulitis with co-morbidity  20 (12-31)  18 (3.3-33)^(a)Median (IQR) in centimeters ^(b)Includes surrounding cellulitis IQR= interquartile range

TABLE 5 Co-morbid conditions (ITT population). Compound 1 LinezolidCondition^(a) (n = 111) (n = 108) Hepatitis C seropositive 46 (43%) 40(37%) Substance abuse 41 (37%) 36 (33%) Diabetes Mellitus 27 (24%) 20(19%) Cardiovascular Disease^(b) 35 (32%) 38 (35%) ^(a)Hepatitis Cseropositive confirmed by serology; other conditions based on patientmedical histories ^(b)Includes coronary artery or peripheral vasculardisease

TABLE 6 Clinical findings. Characteristic Measure Compound 1 (n = 111)Linezolid (n = 108) Erythema None 1 (0.9%) 2 (1.9%) Mild 10 (9.0%)  21(19.4%) Moderate 65 (58.6%) 63 (58.3%) Severe 35 (31.5%) 20 (18.5%)Edema/ None 2 (1.8%) 1 (0.9%) Induration Mild 14 (12.6%) 23 (21.3%)Moderate 63 (56.8%) 57 (52.8%) Severe 32 (28.8%) 25 (23.1%) PurulenceNone 32 (28.8%) 31 (28.7%) Mild 43 (38.7%) 42 (38.9%) Moderate 28(25.2%) 28 (25.9%) Severe 8 (7.2%) 5 (4.6%) Tenderness/ None 1 (0.9%) 0Pain Mild 8 (7.2%) 10 (9.3%)  Moderate 41 (36.9%) 51 (47.2%) Severe 61(55.0%) 45 (41.7%) Fluctuance None 53 (47.7%) 53 (49.1%) Mild 28 (25.2%)27 (25.0%) Moderate 21 (18.9%) 18 (16.7%) Severe 9 (8.1%) 8 (7.4%)Necrotic Tissue None 88 (79.3%) 87 (80.6%) Mild 12 (10.8%) 14 (13.0%)Moderate 9 (8.1%) 5 (4.6%) Severe 2 (1.8%) 0

TABLE 7 Subject disposition. Subject subpopulation Compound 1 (n = 118)Linezolid (n = 116) Intent-to-treat 111 108 Completed Therapy 106(95.5%)  100 (92.6%)  Premature Discontinuation 5 (4.5%) 8 (7.4%)Adverse Event 1 (0.9%) 2 (1.9%) Treatment Failure 1 (0.9%) 0 Lost tofollow-up 3 (2.7%) 6 (5.5%)

TABLE 8 Duration of Treatment (ITT population). Route Compound 1 (n =111)¹ Linezolid (n = 108)¹ IV 4 (2-6) 3 (2-6) Total (IV plus oral) 10(8-12) 10 (7-13) ¹Median (IQR)

TABLE 9 Efficacy - ITT. Clinical Outcome Compound 1 (n = 111) Linezolid(n = 108) Clinical Success 98 (88.3%) 82 (75.9%) Clinical Failure 13(11.7%) 26 (24.1%) Failure 2 (1.8%) 6 (5.6%) Nonevaluable 11 (9.9%)  20(18.5%)

TABLE 10 Efficacy - mITT. Clinical Outcome Compound 1 (n = 84) Linezolid(n = 78) Clinical Success 75 (89.3%) 59 (75.6%) Clinical Failure  9(10.7%) 19 (24.4%) Failure 2 (2.4%) 4 (5.1%) Nonevaluable 7 (8.3%) 15(19.2%)

TABLE 11 Efficacy - clinically evaluable. Clinical Outcome Compound 1 (n= 100) Linezolid (n = 88) Clinical Success 98 (98.0%) 82 (93.2%)Clinical Failure 2 (2.0%) 6 (6.8%)

TABLE 12 Efficacy - microbiologically evaluable. Clinical OutcomeCompound 1 (n = 77) Linezolid (n = 63) Clinical Success 75 (97.4%) 59(93.7%) Clinical Failure 2 (2.6%) 4 (6.3%)

TABLE 13 Microbiology - mITT population. Primary Secondary Share ofBacteria Pathogen Pathogen Total Pathogens Primary (%) MRSA 82 0 82 51MSSA 59 1 60 37 Streptococci 8 13 21 5 (beta and other) Enterococci 5 27 3 Gram-negative 5 16 21 3 rods Anaerobes 1 2 3 1 Total 160 34 194 100

TABLE 14 Distribution of baseline pathogen by treatment (mITTpopulation). Bacteria Compound 1 (n = 84) Linezolid (n = 78) MRSA 44(52.4%) 38 (48.7%) MSSA 31 (36.9%) 29 (37.2%) B-hemolytic Streptococci 7(8.3%) 2 (2.6%) Streptococci, other 4 (4.8%)  8 (10.3%) Enterococci 2(2.4%) 5 (6.4%) Gram-positive, other 0 1 (1.3%) Gram-negative, other 13(15.5%)  8 (10.3%) Anaerobes 0 3 (3.8%)

TABLE 15 Microbiology - clinical outcome (ME). Compound 1 LinezolidSuccess Success Organism (n = 73) Failure (n = 2) (n = 59) Failure (n =4) MSSA 27 2 21 2 MRSA 42 0 30 2 B-Strep 6 0 0 2 GNR 7 2 7 0 ViridansStrep 3 1 6 0 Enterococcus 1 1 3 0 G+ anaerobes 0 0 3 0 Mixed GPC 16 2 92 Mixed 12 2 10 0 GPC/GNR

TABLE 16 Microbiology outcome (ME). Outcome¹ Compound 1 (n = 75)Linezolid (n = 63) Presumed Eradication 71 (94.7%) 58 (92.1%) PresumedPersistence 2 (2.7%) 4 (6.3%) Persistence² 2 (2.7%) 1 (1.6%) ¹PresumedEradication: Clinical success, no pathogen at TOC Presumed Persistence:Clinical failure, no pathogen at TOC Persistence: Clinical success,enrollment pathogen isolated at TOC ²MRSA persisted in all three cases

TABLE 17 Safety and adverse events (AE) by patient. Compound 1 (n = 111)Linezolid (n = 108) Drug Drug Organ System Total Related^(a) TotalRelated^(a) Cardiac 4 0 4 3 Ear 0 0 2 1 Eye 2 0 1 1 GI 21 12 21 13^(b)General 11 5 8 4 Heme 1 0 2 0 Infection 6 0 9 1 Injury 1 0 1 1Investigations 7 3 11 8 Metabolism 9 1 7 2 Musculoskeletal 8 0 2 0Neurologic 12 4 15 7 Psych 5 2 6 3 Renal 2 1 2 0 Reproductive 2 0 1 0Respiratory 3 0 2 0 Skin 12 7 10  6^(c) Vascular 3 0 1 1 None 65 (58.6%)— 53 (49.1%) — Total Patients with 1 or 56 (41.4%) — 55 (50.9%) — moreAE ^(a)Assessed as probably or possibly drug-related by blindedevaluator ^(b)Includes 1 patient discontinued due to heartburn^(c)Includes 1 patient discontinued due to rash

TABLE 18 Safety: ALT (max on treatment). ALT Level Compound 1 LinezolidALT within normal Within normal limits 84 (86.6%) 75 (78.9%) limits atenrollment 1x-2x 12 (12.4%) 14 (14.7%) 2x-3x 0 5 (5.3%) >3x 1 (1.0%) 1(1.1%) ALT abnormal at Within normal limits 1 (7.1%)  2 (16.7%)enrollment¹ NS 11 (78.6%)  8 (66.7%) Increase  2 (14.3%)  2 (16.7%)¹NS: >ULN and <2x baseline. Increase: >2x ULN and 2x baseline NS = Notsignificant

TABLE 19 Safety: ALT (EOT). ALT Level Compound 1 Linezolid ALT withinnormal Within normal limits 86 (93.5%) 79 (87.8%) limits at enrollment1x-2x 6 (6.5%)  9 (10.0%) 2x-3x 0 1 (1.1%) >3x 0 1 (1.1%) ALT abnormalat Within normal limits  2 (15.4%)  4 (36.4%) enrollment¹ NS 11 (84.6%) 7 (63.6%) Increase 0 0 ¹NS: >ULN and <2x baseline. Increase: >2x ULNand 2x baseline EOT = end of treatment

TABLE 20 Safety: ALT (TOC). ALT Level Compound 1 Linezolid ALT withinnormal Within normal limits 85 (94.4%) 75 (94.9%) limits at enrollment1x-2x 5 (5.6%) 4 (5.1%) 2x-3x 0 0 >3x 0 0 ALT abnormal at Within normallimits  3 (23.1%)  5 (41.7%) enrollment¹ NS  9 (69.2%)  6 (50.0%)Increase 1 (7.7%) 1 (8.3%) ¹NS: >ULN and <2x baseline. Increase: >2x ULNand 2x baseline

Total bilirubin was slightly elevated in 2 patients in each group.

SUMMARY OF RESULTS

The ITT populations (111 received compound 1, 108 received linezolid)were comparable in terms of enrollment criteria, disease severity,co-morbidities, and demographics. Mean duration of total treatment andof IV and oral therapy did not differ between compound 1 (9.9, 4.3, 5.6days respectively) and linezolid (9.7, 4.3, 5.4 days, respectively). Theefficacy (clinical success) of compound 1 was 88.3% for the ITTpopulation compared to 75.9% for linezolid. In the clinically evaluablepopulation, the clinical success rates were 98% and 93.2% for compound 1and linezolid, respectively. Bacterial pathogens were cultured atbaseline from ˜74% of each treatment group; over 50% had MRSA. Among themicrobiologically evaluable patients, there were 2 failures in thecompound 1 group, none was associated with MRSA and 4 failures in thelinezolid group, 2 of which were associated with MRSA. Compound 1 waswell tolerated. There were no discontinuations due to adverse events(AEs) for compound 1 (vs 2 for linezolid) and no drug-related serious AEin either group. In both treatment groups the most common drug-relatedAEs were gastrointestinal (12 PTK vs 13 linezolid). GI events associatedwith compound 1 were observed almost entirely during oral therapy, weremild, and did not result in discontinuation of therapy. There were noobserved differences between the treatment groups in hematology or serumchemistry parameters.

The invention claimed is:
 1. A method of treating a human subject forcomplicated Skin and Skin Structure Infections, comprising intravenouslyadministering to said subject an effective amount of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof,such that said subject is treated, wherein gastrointestinal (GI) adverseevents (AEs) associated with treatment are mild, and wherein saidsubject is treated up to and including about 14 days, up to andincluding about 10 days, up to and including about 9 days, up to andincluding about 8 days, or up to and including about 7 days, such thatsaid subject is treated.
 2. A method of treating a human subject forcomplicated Skin and Skin Structure Infections, comprising intravenouslyadministering to said subject an effective amount of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof,such that said subject is treated, wherein gastrointestinal (GI) adverseevents (AEs) associated with treatment are mild, wherein said9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is administeredintravenously, followed by an oral administration, and wherein said9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is administeredintravenously for about 2-6 days, and total treatment period includingintravenous and oral administration is about 8-12 days.